Phosphate (phosphorus) is critical for a variety of biologic and cellular processes. Phosphate along with calcium is a major component of the skeletal system, providing mineral strength to bone. Phosphate is also an integral component of nucleic acids as well as the phosphate bonds of the cellular energy molecule ATP. Phosphate functions as a buffer in bone, serum, and urine. Accordingly, physiological levels of phosphate in the blood are careful regulated by a variety of organ systems of in the body
The bulk of total body phosphate (85%) is in the bone as part of the mineralized extracellular matrix. About 300 mg of phosphate enters and exits bone tissue each day. Excessive losses or failure to add phosphate to bone leads to osteomalacia. The kidneys along with parathyroid hormone (PTH), which is secreted by the parathyroid gland, play an important role in phosphate homeostasis by controlling the excretion of phosphate, while the digestive tract and the hormone Vitamin D play yet another important role in phosphate homeostasis by controlling its absorption from the diet.
The kidneys provide the primary route of excretion for excess phosphorus absorbed from ingested food or liberated from bone. Consequently in chronic kidney disease (CKD) patients as kidney function worsens elevation in blood levels of serum phosphorus directly stimulate PTH secretion by the parathyroid glands, which can then further exacerbate the homeostasis by liberating more phosphorus from bone. Since failing kidneys can no longer adequately handle the burden of excess phosphorus, CKD patients must control their diet to reduce phosphate intake. Increases in serum phosphorus level begin early in CKD disease progression in Stage 3 and Stage 4 and can get progressively worse as kidney function declines. Stage 5 CKD patients (also referred to as end stage renal disease or ESRD) usually under go regular dialysis to remove excess toxins and metabolites, including phosphorus, and yet also require treatment with phosphate-binding agents in an attempt to bind-up dietary phosphates and thereby prevent systemic absorption as a way to lower serum phosphorus to acceptable levels. In the U.S., approximately 90% of dialysis patients are treated with a phosphate control product.
Elevated serum phosphorus has been linked to the development and progression of hyperparathyroidism, bone disease such as osteodystropy and soft tissue mineralization and is associated with an increased risk of death in hemodialysis patients (Block et al., 1998, Am J. Kidney Dis, 31:607-617; Block et al., 2000, Am J. Kidney Dis, 35:1226-1237; Palmer et al., 2011, JAMA, 305:1119-1127). Severe hyperphosphatemia (serum phosphate level >6.5 mg/dL (>2.10 mmol/L)) has been associated directly with increased overall and cardiovascular mortality in hemodialysis (HD) patients (Palmer et al., 2011, JAMA, 305:1119-1127), and even moderate hyperphosphatemia (3.0 to 5.0 mg/dL) is associated with increased cardiovascular risk in these patients. Currently, clinical guidelines recommend maintaining phosphate levels within normal range (3.0 to 5.0 mg/dL (0.97 to 1.61 mmol/L)). However, even moderate to severe hyperphosphatemia (phosphate, 5.01 to 6.5 mg/dL (1.62 to 2.10 mmol/L)) needs to be addressed since it is an independent mortality risk factor in HD patients, and phosphate binders therapy alone do not always reduce serum phosphorus levels sufficiently.
Hyperphosphatemia also leads to secondary hyperparathyroidism (SHPT) and elevated blood levels of PTH by: (a) lowering the levels of ionized calcium; (b) interfering with the production of 1,25(OH)2D3; and (c) by directly affecting PTH secretion. These processes lead to high-turnover bone disease and other adverse consequences of excess PTH.
Current clinical guidelines recommend maintaining phosphate levels within normal range (3.0 to 5.0 mg/dL (0.97 to 1.61 mmol/L)). It is generally accepted that control of serum phosphorus will lead to improved clinical outcomes and survival in hemodialysis patients. Approaches to lowering serum phosphorus include dialysis, dietary phosphorus restriction and oral phosphate binders.
Serum phosphate declines rapidly in the first 1-2 hours of dialysis and then a plateau is reached during which serum phosphate remains relatively constant. After dialysis, serum phosphorus concentration rises quickly in the first few hours, typically reaching a concentration approximating the pre-dialysis value 6-8 hours later (Haas et al., 1991, Nephrol Dial Transplant, 2:108-113; Sugisaki et al., 1983 Trans Am Soc Artif Intern Organs, 29:38-43). This phenomenon has been referred to as “phosphate rebound.” In some cases, phosphate rebound produces higher phosphate levels than were initially present.
The control of phosphorus often remains unsatisfactory in dialyzed patients. Accordingly, there is a continuing need for methods for treating hyperphosphatemia in hemodialysis patients. In particular, methods for reducing phosphate rebound are desired.